Pseudomonas aeruginosa is a common environmental microorganism that has acquired the ability to take advantage of weaknesses in the host defenses to become an opportunistic pathogen in humans. It is the most common Gram-negative cause of hospital-acquired infections. In general, P. aeruginosa infections are especially troublesome due to the fact that this bacterium continues to acquire resistance to commonly-used antibiotics. P. aeruginosa is a part of the drug-resistant ESKAPE microbe group, which considered one of the biggest threats infectious diseases today. Notably, it is intrinsically resistant to a number of antibiotics due to its multidrug efflux pump systems, and a bacterial envelop that has low permeability. These attributes, plus a predilection towards hypermutation and efficient horizontal gene transfers of antibiotic resistance genes give rise to infections that become refractory to antibiotic therapy.
Pseudomonas aeruginosa Infections.
P. aeruginosa is the most common Gram-negative pathogen isolated from chronic wound infections. Infections of the dermis, including burns, surgical-site infections and non-healing diabetic foot ulcers affect over a million people, cause thousands of amputations and deaths and cost billions of dollars in direct medical costs in the United States annually. The microbial populations of these infections are biofilm-associated and display increased tolerance to antimicrobials.
In burn wound infections, P. aeruginosa is the most common Gram-negative isolated and is associated with very high mortality. The American Burn Association estimates that approximately 500,000 individuals in the United States are treated for thermal injury each year, resulting in over 4,000 deaths. Worldwide, the numbers are significantly larger, especially in areas of conflict. As thermal injury removes or impairs the body's natural barrier to microbes, the cause of death in over 75% of these burned individuals is infection. While not as dramatic, secondary sepsis, originating from infected wounds, affects trauma patients and those with surgical-site infections. Approximately 10% of burn patients become infected with P. aeruginosa and of those, up to 75% die of septicemia. Sepsis is the most common cause of death among ICU patients, and ranks 10th among all patients.
Most prominent is the role of P. aeruginosa in patients suffering from cystic fibrosis (CF). CF is the most common lethal inherited genetic disorder that follows an autosomal recessive inheritance pattern in Caucasian people. Approximately 30,000 people in the United States suffer from CF. Due to impaired lung defense functions, CF patients are vulnerable targets for P. aeruginosa. As a result, infections with P. aeruginosa, and the damage caused by the inflammatory infection process leads to death in more than 90% of CF patients.
OprF and OprI.
Both proteins are P. aeruginosa outer membrane proteins that are surface exposed and antigenically conserved in various strains of P. aeruginosa. Antibodies against OprF are associated with protection in animal models and are present following immunization in humans. It has also been reported that OprF function is required for full P. aeruginosa virulence as it is a modulator of quorum sensing. The binding of OprF to interferon-γ (IFN-γ) has been shown to up-regulate another adhesin, LecA, through quorum sensing. Activation of IFN-γ also increased expression of pyocyanin, which is another quorum-sensing-related virulence product. Activation of LecA and pyocyanin leads to the disruption of epithelial cell function. OprF is essential for microaerobic growth of P. aeruginosa, and expression is also imperative for the formation of anaerobic biofilms. OprF mutants are unable to adhere to animal cells and lack the ability to secrete ExoT and ExoS toxins via the type III secretion system. An OprF mutant was deficient in the production of signal molecules N-(3-oxododecanoyl)-1-homoserine lactone and N-butanoyl-1-homoserine lactone, both of which regulate the timing and production of pyocyanin, elastase, lectin PA-1L and exotoxin A. There, there is a need in the art for effective anti-infective agents.